Cyclohexylbenzamide derivatives, their preparations and their use as gastrointestinal stimulants

ABSTRACT

Novel N-cyclohexylbenzamide derivatives of formula:   &lt;IMAGE&gt; (I) where R1 represents an alkoxy radical capable of cyclizing with the aromatic ring; R2, R3 and R4 each independently represent hydrogen, a halogen or an alkoxy, amino, alkylamino or alkyl-carbonylamino group, and Z represents a differently substituted piperidinyl group; and their addition salts with pharmaceutically acceptable acids. The compounds of formula I are powerful gastrointestinal motility stimulants.

Numerous orthopamides are known for various pharmacological properties, such as, for example, the neuroleptic agents derived from Sulpiride (U.S. Pat. No. 3,342,826) or the anti-emetic agents and gastric motility stimulants such as Metoclopramide (BE-A-620,543). The latter product is known to act on the dopaminergic processes of the central nervous system.

More recent compounds of the benzamide family, such as Cisapride (EP-A-076,530) or Renzapride (EP-A-094,742) are known for their activity on the digestive motility in the absence of central antidopaminergic effects.

In addition, compounds corresponding to the general formula ##STR2## in which R is a tertiary amino group, in particular a piperidino group, and R' is an alkoxy group in the para- or meta-position on the benzamide ring, are known for their anticonvulsant properties (GB-A-1,015,921).

We have now discovered that the compounds which are represented by the general formula (I) defined below and which differ from the above compounds in particular in that they contain a polysubstituted aromatic ring and in particular an alkoxy group in the ortho-position are powerful gastro-intestinal motility stimulants and devoid of central dopaminergic antagonistic activity, while the compounds described which do not have this substitution do not have such an activity. By way of example, a compound A of the type described in GB-A-1,015,921, corresponding to the general formula I but with R₁ ═R₃ ═R₄ ═H and R₂ ═4-pentyloxy do not show any activity on the intestinal motility at the highest dose used to test the compounds according to the invention.

The present invention thus relates to novel benzamides corresponding to the general formula (I) ##STR3## in which:

R₁ is selected from C₁ -C₄ alkoxy, methoxy (C₁ -C₃ alkoxy), C₃ -C₄ alkenyloxy and C₅ -C₆ cycloalkoxy groups, or R₁ and R₂, in the 3-position, together and with the aromatic ring to which they are bonded form a 2,3-dihydrobenzofuran ring,

R₂ R₃ and R₄ are selected independently of one another from a hydrogen atom, a halogen atom and hydroxy, C₁ -C₃ alkoxy, amino,(C₁ -C₃ alkyl)amino or di(C₁ -C₃ alkyl) amino and (C₁ -C₃ alkyl)carbonylamino groups, and

Z is selected from piperidinyl groups and piperidinyl groups substituted in the 4-position by a hydroxy , C₁ -C₃ alkoxy, hydroxyethyl, (C₁ -C₃ alkoxy)ethyl and (C₁ -C₃ alkoxy)methyl groups, a C₁ -C₄ alkyl group or two C₁ -C₃ alkyl groups, their N-oxides, in particular those in which the N-oxide is carried by Z, and their addition salts with pharmaceutically acceptable acids.

The present invention encompasses the stereoisomers of cis relative configuration and tran relative configuration formed by the substituents of the cyclohexyl ring, as well as the corresponding enantiomers.

In the present invention, alkyl or alkoxy group denotes either straight-chain or branched groups or groups having a cyclic part.

In the present invention, "pharmaceutically acceptable salts" denotes the addition salts with acids which give the biological properties of the compounds without having an undesirable effect. These salts may be, in particular, those formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid or phosphoric acid; acid metal salts, such as disodium orthophosphate and monopotassium sulphide, and organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, oxalic acid, fumaric acid, lactic acid, succinic acid, tartaric acid, malic acid and pamoic acid.

The preferred compounds of formula I are those which have an alkoxy substituent, in particular a methoxy, ethoxy or cyclopropylmethoxy group, in the 2-position, an amino substituent in the 4-position and chloro in the 5-position on the aromatic ring.

Amongst these benzamides, the compounds of formula (I) in which Z is a piperidino group, preferably substituted in 4-position by one or two methyl groups or by a hydroxyl group, are more particularly preferred.

The preferred compounds therefore have the structure (IV) or (V). ##STR4## in which R₇ ═CH₃, R₁₀ ═H or R₇ ═CH₃ ═R₁₀ or R₇ ═OH, R₁₀ ═H and R₁ ═OCH₃, OC₂ H₅ or cyclopropylmethoxy.

The compounds of formula (I) may be obtained by a condensation reaction between a benzoic acid of formula VI, where R₁, R₂, R₃ and R₄ have the same definitions as above, and a cyclohexylamine of formula (VII) of cis or trans configuration with Z having the same definitions as in formula (I) in accordance with the equation ##STR5##

The coupling agent may be carbonyldiimidazole or dicyclohexylcarbodiimide used in solvents such as methylene chloride or tetrahydrofuran or even pyridine.

If the benzoic acid of the formula VI does not carry a basic amino or alkylamino functional group, it may be activated in the form of the acid chloride by the action of thionyl chloride in a solvent such as toluene, before reaction with the amine of formula VII.

The amine of formula VII may be obtained by several different routes leading either to the diastereoisomer of cis configuration of formula VII' or to the diastereoisomer of trans configuration of formula VII''.

Route 1

The compound of formula VII' may be obtained by reaction of the cis-amine of formula VIII' with the aid of a hydride such as lithium aluminium hydride in tetrahydrofuran ##STR6##

Similarly, the compound of formula VII'' may be obtained by reduction of the amide of formula VIII'' ##STR7##

The compounds VIII are obtained in three steps from the corresponding β-amino acids in accordance with the following equation: ##STR8##

Step 1 consists in protecting the primary amine by an acyl group such as trifluoroacetyl, as already described in the literature (Act. Chim. Acad. Scient. Hung 99 (2), 175-192 (1979)) or urethane group, such as benzyloxycarbonyl or t-butoxycarbonyl, or any other group commonly used in peptide synthesis.

Step 2 comprises a condensation reaction of the group Z, either by one of the methods described for the preparation of (I) or even by the intermediate formation of a mixed anhydride, obtained from chloroformates.

Step 3 consists in removing the protection from the amine functional group, using an alkaline medium in the case of a trifluoroacetyl, a catalytic hydrogenation in the case of a benzyloxycarbonyl group, or trifluoroacetic acid in methylene chloride in the case of a t-butoxycarbonyl group.

The starting β-amino acids of cis or trans relative configuration are obtained by the methods already described in the literature.

The preparation of the optically pure compounds VII may be carried out by stereoselective crystallisation of the N-protected, for example N-benzoylated, β-amino acids, in the form of a salt obtained with the aid of an optically active amine, such as cinchonodine. A resolution of this type is described in J. Chem. Soc. (1970), 1597-1600. The optically pure β-amino acid is then converted to diamine VII by the sequence of following reactions: ##STR9##

Step 1 comprises a condensation reaction of the group Z by the methods already described. Step 2 consists in selective reduction of the tertiary amide functional group by a hydride such as AILiH Step 3 consists in hydrolysing the benzoyl group in an aqueous acid medium. The sequence of reactions is carried out on one or the other enantiomers.

Another method for obtaining optically pure compounds consists in carrying out a stereoselective hydrolysis of dimethyl 1,2-cyclohex-4-enedicarboxylate with the aid of a lipase such as pig liver lipase. Optically pure β-amino acids are obtained after Curtius arrangement carried out on the acid ester.

A methodology of this type is described in Tetrahedron Letters (1984), 25, 2557-2560. The cyclohexene double bond is reduced by hydrogenation in the presence of a catalyst, such as palladium-on-charcoal. This step may be carried out at any time in the sequence of operations, depending on the protective groups used. These β-amino acids are converted to diamine VII by the methods described above.

Route 2

The compounds of formula VII may also be obtained by a Mannich reaction on cyclohexanone, followed by a reductive amination reaction proceeding either via the oxime or via an imine such as that obtained with benzylamine, in accordance with the equation: ##STR10##

In this case a mixture of the cis and trans compounds is obtained, the proportions of which vary with the reducing agent used in the final step. By way of example, the oxime obtained from the ketone of formula (IX) predominantly yields a trans-amine VII'' by reduction with the aid of sodium in isoamyl alcohol and predominantly yields a cis-amine VII' following reduction using the hydride AlLiH₄.

Route 3

The compounds of general formula VII'' may also be obtained from the ketone IX by reduction with the aid, for example, of K selectride (of formula K(s-Bu)-3BH) in tetrahydrofuran.

The cis-alcohol obtained is then activated, for example via a mesylate, and a functional group capable of generating a primary amine, such as an azide or phthalimide group, is then introduced as a substituent. The precursor is then converted to amine by the methods known from the literature. The reaction equation is as follows: ##STR11## Where Q=N₃, phthalimide.

The following examples illustrate the preparation of the compounds of formula I.

EXAMPLE 1

N-[cis-2-(4-methylpiperidinomethyl)cyclohexyl]-4-amino-5-chloro-2-methoxybenzamide.

Carbonyldiimidazole (2.95 g; 18.2 mmoles) is added to a solution of 4-amino-5-chloro-2-methoxybenzoic acid (3.67 g; 18.2 mmoles) in THF (50 ml).

After stirring for one hour at ambient temperature, cis 2-(4-methylpiperidinomethyl) cyclohexylamine (3.83 g; 18.2 mmoles) is added as a solution in THF (15 ml). The reaction mixture is stirred overnight at ambient temperature. The mixture is evaporated under reduced pressure. The residue is taken up in methylene chloride and washed with an 8% aqueous solution of sodium bicarbonate and then with water.

The organic phase is dried over sodium sulphate and the solvent is driven off under reduced pressure to give crystals (5.87 g; 83%), which are recrystallised from isopropyl ether/acetone (8/2) mixture.

Melting point: 141°-142° C.

IR: (C═O): 1638 cm⁻¹ (CHCl₃)

EXAMPLE 2

N-[cis-2-(4-methylpiperidinomethyl)cyclohexyl]-4-amino-5-chloro-2-methoxybenzamide hydrochloride hydrate.

The product obtained from the preceding example (4.56 g) is dissolved in absolute ethanol (15 ml) and treated with a 4 N solution of hydrochloric acid in ethyl ether (4.3 ml). The mixture is concentrated and the hydrochloride is crystallised in the form of the hydrate (5.4% of water) by the addition of water (30 ml).

Melting point: 58°-145° C. (decomposition).

IR: (C═O): 1627 cm⁻¹ (KBr).

EXAMPLE 3

N-[trans-2-(4-methylpiperidinomethyl)cyclohexyl]-4-amino-5-chloro-2-methoxybenzamide dihydrochloride.

The product is prepared as in Example 1 using trans-2-(4-methylpiperidinomethyl)cyclohexylanine. The product is purified by chromatography on a silica column eluting with a methylene chloride/ethyl acetate/methanol/ammonia system (85/15/5/0.3). The oil obtained is treated with chloroethane, the solvent is evaporated and the residue is taken up in acetone to give crystals.

m.p.: 182°-184° C.

IR: (C═O): 1646 cm⁻¹ (KBr).

EXAMPLE 4

N-[cis-2-(4,4-dimethylpiperi-dinomethyl)cyclohexyl]-4-amino-5-chloro-2-methoxybenzamide hydrochloride hemihydrate.

The product is prepared as in Example 3 from cis-2-(4,4-dimethylpiperidinomethyl)cyclohexylamine.

m.p.: 132°-153° C. (dec.)

IR: (C═O): 1617 cm⁻¹ (CHCl₃)

The other compounds are obtained by identical methods using benzoic acid and the corresponding cyclohexylamine derivative. For 3-chloro-2,4,6-trimethoxybenzoic acid, the acid chloride is used as intermediate active species. The characteristics of these compounds are listed in Table I.

                                      TABLE 1                                      __________________________________________________________________________                                          Melting                                   Ex. No.                                                                             R.sub.1,R.sub.2,R.sub.3,R.sub.4                                                              Z (configuration)                                                                           Salt Point °C.                                                                      Purification                                                                            IR                        __________________________________________________________________________                                                          cm.sup.-1                  5   4-amino-5-chloro-2-methoxy                                                                   piperidino (cis)                                                                            base 153-170 (dec)                                                                         Chromatography                                                                          1637, 1617                                                                     (CHCl.sub.3)                                                          SiO.sub.2                           6     "           piperidino (trans)                                                                          base 100-113                                                                               Chromatography                                                                          1604, 1616                                                                     (CHCl.sub.3)                                                          SiO.sub.2                           7     "           4-ethylpiperidino (cis)                                                                     HCl  162-173 (dec)                                                                         Acetone/ 1616 (CHCl.sub.3)                                                     acetonitrile                        8     "           4-propylpiperidino (cis)                                                                    HCl  192 (dec)                                                                             EtOH/H.sub.2 O                                                                          1616 (CHCl.sub.3)          9     "           4-t-butylpiperidino (cis)                                                                   HCl  140-167 (dec)                                                                         H.sub.2 O                                                                               1623 (KBr)                                                H.sub.2 O                                      10     "           3,5-dimethylpiperidino (cis)                                                                HCl  142-152 (dec)                                                                         H.sub.2 O                                                                               1628 (KBr)                                                H.sub.2 O                                      11     "           4-methyl-4-ethylpiperidino                                                                  HCl  185-190                                                                               H.sub.2 O                                                                               1623 (KBr)                                   (cis)        1.5 H.sub.2 O                                  12     "           4-methoxyethylpiperidino                                                                    base  98- 106                                                                              petroleum ether/                                                                        1637-1617                                                                      (CHCl.sub.3)                                 (cis)                    ethyl acetate                      13   3-chloro-2,4,6-trimethoxy                                                                    piperidino (cis)                                                                            HCl  220-230                                                                               acetone  1623 (KBr)                14     "           piperidino (trans)                                                                          base 212-214 (dec)                                                                         chromatography                                                                          1648 (CHCl.sub.3)                                                     SiO.sub.2                          15     "           4-methylpiperidino (cis)                                                                    HCl  228-236                                                                               chromatography                                                                          1685-1596 (wide)                                                      Al.sub.2 O.sub.3                                                                        (KBr)                     16     "           4-methylpiperidino (trans)                                                                  base 120-121                                                                               chromatography                                                                          1648 (CHCl.sub.3)                                                     SiO.sub.2                          __________________________________________________________________________                                       Melting                                      No.                                                                               R.sub.1,R.sub.2,R.sub.3,R.sub.4                                                               Z (configuration)                                                                           Salt                                                                              Point °C.                                                                     Purification                                                                           IR (cm.sup.-1)                                                                       [α].sub.D.sup.                                                           20 ° = (C         __________________________________________________________________________                                                           %)                       17 4-amino-5-chloro-2 ethoxy                                                                     4-methyl piperidino                                                                         base                                                                              137,5-138,5                                                                          Acetone/ethyl                                                                          1636-1616                                                                            /                                          (cis)                 ether   (CHCl.sub.3)                   18 4-amino-5-chloro-2-cyclopropyl                                                                4-methyl piperidino                                                                         HCl                                                                               220-278 dec                                                                          H.sub.2 O                                                                              1616 (KBr)                                                                           /                           methoxy        (cis)                                                        19 4-amino-5-chloro-2 propyloxy                                                                  4-methyl piperidino                                                                         HCl                                                                               213-241 dec                                                                          H.sub.2 O                                                                              1615 (KBr)                                                                           /                                          (cis)                                                        20 4-amino-5-chloro-2 ipropyloxy                                                                 4-methyl piperidino                                                                         HCl                                                                               126-135 dec                                                                          H.sub.2 O                                                                              1627 (KBr)                                                                           /                                          (cis)                                                        21 4-amino-5-chloro-2-allyloxy                                                                   4-methyl piperidino                                                                         HCl                                                                               144-147                                                                              H.sub.2 O                                                                              1618 (KBr)                                                                           /                                          (cis)                                                        22 4-amino-5-chloro-2-methoxy ethoxy                                                             4-methyl piperidino                                                                         HCl                                                                               191-258 dec                                                                          H.sub.2 O                                                                              1614 (KBr)                                                                           /                                          (cis)                                                        23 4-amino-5-chloro-2-methoxy                                                                    4-methyl piperidino (R,R)                                                                   HCl                                                                               188-224 dec                                                                          H.sub.2 O                                                                              1624 (KBr)                                                                           -97,8 (1, MeOH)          24 4-amino-5-chloro-2-methoxy                                                                    4-methyl piperidino (S,S)                                                                   HCl                                                                               187-223 dec                                                                          H.sub.2 O                                                                              1627 (KBr)                                                                           +98,3 (1, MeOH)          25 4-amino-5-chloro-2-cyclo-                                                                     4-methyl piperidino (R,R)                                                                   base                                                                              151-153                                                                              CH.sub.2 Cl.sub.2 /Et.sub.2                                                            1636-1617                                                                            -65,8 (1, MeOH)             propyl methoxy                               (CHCl.sub.3)                   26 4-amino-5-chloro-2-cyclo-                                                                     4-methyl piperidino                                                                         HCl                                                                               239-258 dec                                                                          H.sub.2 O                                                                              1624 (KBr)                        pentyloxy      (cis)                                                        27 4-amino-5-chloro-2-isobutyloxy                                                                4-methyl piperidino                                                                         HCl                                                                               136-143 dec                                                                          H.sub.2 O                                                                              1627 (KBr)                                                                           /                                          (cis)                                                        __________________________________________________________________________                                           Melting                                  No. R.sub.1,R.sub.2,R.sub.3,R.sub.4                                                                Z (configuration)                                                                            Salt                                                                               Point °C.                                                                      Purification                                                                              IR                     __________________________________________________________________________                                                             (cm.sup.-1)            28  4-amino-5-chloro-2-methoxy                                                                     4-hydroxypiperidino                                                                          HCl 254-263 dec                                                                           acetone/water                                                                             1629 (KBr)                                 (cis)                                                      29    "             4-ethoxypiperidino                                                                           HCl 160-166                                                                               H.sub.2 O  1618 (KBr)                                 (cis)                                                      30    "             4-methoxymethyl-                                                                             base                                                                               148-149                                                                               acetone/petroleum                                                                         1638-1617                                  piperidino (cis)         ether      (CHCl.sub.3)           31    "             4-hydroxyethyl-                                                                              HCl 138-143                                                                               acetone    1629 (KBr)                                 piperidino (cis)                                           __________________________________________________________________________      ##STR12##                                                                                                           Melting                                  No. Ar               Z (configuration)                                                                          Salt Point °C.                                                                       Purification                                                                           IR                       __________________________________________________________________________                                                           (cm.sup.-1)              32  7-(2,3-dihydro)benzofuranyl                                                                     4-methylpiperidino                                                                         HCl  177-181 acetone 1643 (KBr)                                    (cis)                                                     33  7-(2,3-dihydro)benzofurnayl                                                                     4-hydroxypiperidino                                                                        HCl  233-238 dec                                                                            H.sub.2 O                                                                              1651 (CHCl.sub.3)                             (cis)                                                     __________________________________________________________________________

The following examples illustrate the preparation of the cyclohexylamines of formula VII.

EXAMPLE A

Cis-2-(4-methylpiperidinomethyl)cyclohexylamine.

a) 1-[cis(2-trifluoroacetamidocyclohexylcarbonyl)]-4-methylpiperidine.

Cis-2-trifluoroacetamidocyclohexanecarboxylic acid chloride (8.61 g; 33 mmoles) in solution in benzene (50 ml) is treated dropwise with 4-methylpiperidine (8.3 g; 83 mmoles) dissolved in benzene (20 ml). The reaction mixture is kept at ambient temperature for 1 h 30 before evaporating the solvent. The residue is taken up in chloroform and the organic phase is washed with water, dried over sodium sulphate and then evaporated under reduced pressure. The product obtained is recrystallised from a benzene/petroleum ether mixture. m.p.: 135.5° C.

IR: (C═O): 1718-1621.5 cm⁻¹ (CHCl₃)

b) 1-[Cis(2-aminocyclohexylcarbonyl]-4-methylpiperidine.

1-[Cis(2-trifluoroacetamidocyclohexyl)carbonyl]-4-methylpiperidine (8.8 g: 0.027 mol) is dissolved in 95% ethanol (250 ml) and a 1 N solution of sodium hydroxide in 95% ethanol (50 ml; 0.05 mol) is then added.

The reaction mixture is stirred for 48 h at ambient temperature and then evaporated under reduced pressure. The residue is taken up in chloroform, washed with 1N NaOH and the organic phase is dried over Na₂ SO₄ and evaporated to give a yellowish oil.

IR (C═O): 1621 cm⁻¹ (CHCl₃)

c) Cis-2-(4-methylpiperidinomethyl)cyclohexylamine.

1-[Cis-(2-aminocyclohexyl)carbonyl]-4-methylpiperidine (6.57 g; 0.0293 mol) is dissolved in tetrahydrofuran (25 ml) and added dropwise to a suspension of AlLiH₄ (2.22 g; 0.0586 mol) in tetrahydrofuran (50 ml). At the end of the addition, the reaction mixture is refluxed for 24 h and then hydrolyzed by carefully adding water (2.3 ml), then a 15% sodium hydroxide solution (2.3 ml) and then water (5 ml).

The aluminium salts are removed by filtering off and the tetrahydrofuran is evaporated under vacuum. The residue is taken up in an acid solution rendered alkaline using a 15% sodium hydroxide solution and extracted with chloroform. The organic phase is dried over Na₂ SO₄ and evaporated under vacuum. The residue is purified by distillation.

b.p (27 Pa): 86°-87° C.

EXAMPLE B

Cis-2-(4,4-dimethyl-piperidinomethyl)cyclohexylamine.

a) 1-[Cis-2-trifluoro-acetamidocyclohexyl)-carbonyl]-4,4-dimethylpiperidine.

The product is obtained using the method described in Example A a) using 4,4-dimethylpiperidine. The residual oil is crystallised from a petroleum ether/ethyl acetate (80/20) mixture. m.p.: 97°-106° C. IR (C═O): 1717.8-1622.0 cm₋₁ (CHCl₃)

b) 1-[Cis (2-aminocyclohexyl)carbonyl]-4,4-dimethylpiperidine.

The product obtained in a) is detrifluoroacetylated using the method described in Example A b) to give an oil.

IR (C═O): 1621 cm⁻¹ (ChCl₃).

c) Cis-2-(4,4-dimethyl-piperidinomethyl)cyclohexylamine.

1-[Cis-(2-aminocyclohexyl)carbonyl]-4,4-dimethylpiperidine is reduced by AlLiH₄ using the procedure described in Example A c). The oil obtained is distilled. b.p. (53 Pa): 112° C.

The other cis cyclohexylamine derivatives are obtained by the same procedures and are reported in Table II.

                                      TABLE II                                     __________________________________________________________________________                          ##STR13##                                                                                       ##STR14##                                                                                ##STR15##                      Example             a)               b)        c)                              No.  Z              m.p.* (°C.)                                                                   IRυ (CO)cm.sup.-1                                                                 IRυ (CO) cm.sup.-1                                                               b.p.** °C.               __________________________________________________________________________                                                    (Pa)                            C    1-piperidinyl  134-137                                                                              1717; 1620 (CHCl.sub.3)                              D    1-(4-ethyl) piperidinyl                                                                       92-96 1719; 1621.5 (CHCl.sub.3)                                                                 1621.6 (CHCl.sub.3)                                                                      125 (27)                        E    1-(4-propyl)piperidinyl                                                                       113-114                                                                              1718; 1621.7 (CHCl.sub.3)                                                                 1621.7 (CHCl.sub.3)                                                                      125 (27)                        F    1-(4-t-butyl)piperidinyl                                                                      151-152                                                                              1719; 1621.7 (CHCl.sub.3)                                                                 1622 (CHCl.sub.3)                                                                        150 (66)                        G    1-(4-ethyl-4-methyl)piperidinyl                                                               91-94 1718.3; 1621.7 (CHCl.sub.3)                                                               1621.7 (CHCl.sub.3)                                                                      150 (53)                        H    1-(3,5-dimethyl)piperidinyl                                                                   118   1716; 1629 (KBr)                                                                          1623 (CHCl.sub.3)                         I    1-(4-methoxyethyl)piperidinyl                                                                 94.5  1718; 1622 (CHCl.sub.3)                                                                   1622 (CHCl.sub.3)                                                                        125 (53)                        __________________________________________________________________________                            ##STR16##                                                                                     ##STR17##                                                                               ##STR18##                       Example                                                                        No.  Z                Melting point °C.                                                                IR δ cm.sup.-1                                                                 IR δ cm.sup.-1                                                                    b.p.                             __________________________________________________________________________     J    1-(4-hydroxy)piperidinyl                                                                        135      1718-1625                                                                            1624     ND oil                                                          (CHCl.sub.3)                                                                         (CHCl.sub.3)                              K    1-(4-hydroxyethyl)piperidinyl                                                                   oil      1717-1623                                                                            1622     ND oil                                                          (CHCl.sub.3)                                                                         (CHCl.sub.3)                              L    1-(4-ethoxy)piperidinyl                                                                         94-96    1719-1624                                                                            1625     137.5° C.                                                (CHCl.sub.3)                                                                         (CHCl.sub.3)                                                                            (0.4 mmHg)                       M    1-(4-methoxymethyl)-piperidinyl                                                                 132-133  1718-1624                                                                            1624     ND oil                                                 (CHCl.sub.3)                                                                            (CHCl.sub.3)                                    __________________________________________________________________________      *Kofler stage                                                                  **Buchi bulb oven                                                              ND: Not distilled                                                        

EXAMPLE N

Trans-2-(4-methylpiperidinomethyl)cyclohexylamine.

a) 2-(4-methylpiperidinomethyl)cyclohexylamine.

Cyclohexanone (47.5 g; 0.484 mol) is dissolved in 95% ethanol containing formaldehyde (36 g of a 37% aqueous solution), hydrochloric acid (1.7 ml of a 37% aqueous solution), hydrochloric acid (1.7 ml of a 36% aqueous solution) and 4-methylpiperidine (40 g; 0.4 mol). the solution is refluxed for four hours. The ethanol is evaporated under vacuum and the residue is taken up in a 2N hydrochloric acid solution. The aqueous phase is washed with ether, rendered alkaline using a 15% aqueous sodium hydroxide solution and then extracted with methylene chloride. The organic phase is dried over Na₂ SO₄ and the solvent is then driven off under vacuum. The oil obtained is distilled. b.p. (27 Pa): 85°-90° C.

IR (C═O): 1706 (CHCl₃)

b) 2-(4-methylpiperidinomethyl)cyclohexanone oxime.

2-(4-methylpiperidinomethyl)cyclohexanone (20.8 g; 0.1 mol) is dissolved in ethanol (100 ml). Hydroxylamine hydrochloride (7.54 g: 0.109 mol) dissolved in water (15 ml) is added to this solution. The reaction mixture is stirred for 1 h at ambient temperature. The solvent is evaporated under vacuum and the residue is taken up in chloroform and washed with a 2 N aqueous sodium hydroxide solution. The organic phase is dried over Na₂ SO₄ and evaporated to give a white powder.

m.p.: 113°-116.5° C.

c) 2-(4-methylpiperidinomethyl)cyclohexylamine.

The oxime (13.5 g; 0.06 mol) obtained in the preceding example is dissolved in amyl alcohol (200 ml). Sodium (8.33 g; 0.36 mol) is added in small amounts so as to maintain gentle boiling. At the end of the addition, the reaction mixture is cooled and then acidified using a 2N aqueous HCl solution. The aqueous phase is extracted with ethyl acetate, rendered alkaline using a 15% sodium hydroxide solution and then extracted with methylene chloride. The organic phase is dried over Na₂ SO₄ and then evaporated. The residual oil is distilled. b.p. (27 Pa): 94°-98° C. The product obtained contains about 75% of trans-2-(4-methylpiperidinomethyl)-cyclohexylamine. The pure diastereoisomer is isolated at the benzamide stage.

EXAMPLE O

(S,S)- and (R,R)-2-(4-methylpiperidinomethyl)cyclohexylamine.

a) 1-[2(R)-benzamide-(S)-cyclohexylcarbonyl]-4-methylpiperidine.

2-(R)-benzamide-(S)-cyclohexylcarboxylic acid (8.87 g) is dissolved in 200 ml of tetrahydrofuran. After adding carbonyldiimidazole (5.82 g), the reaction mixture is stirred for 1 h 30 at ambient temperature. A solution of 4-methylpiperidine in 20 ml of tetrahydrofuran is added and the reaction mixture is stirred for a further 48 hours. The solvent is driven off under vacuum and the residue is taken up in methylene chloride. The organic phase is washed with twice 50 ml of 1N HCl, twice 50 ml of 1N NaOH and then twice 50 ml of water, dried over Na₂ SO₄ and evaporated under reduced pressure. 11.16 g (94%) of oil are obtained. [α]₅₇₈ ²⁰ =-47.9° (C=1, MeOH);

IR: =1731 weak, 1648, 1620 cm⁻¹ (CHCl₃)

a) 1-[2(S)-benzamido-(R)-cyclohexylcarbonyl]-4-methylpiperidine is obtained from the antipode as here by the same procedure. [α]₅₇₈ ²⁰ =+49.2°; (c=1, MeOH);

IR=1730 (weak), 1648, 1619 cm⁻¹ (CHCl)₃.

b) N-benzoyl-2(R)-(4-methylpiperidinomethyl)-(R)-cyclohexylamine.

The product obtained in step a) (10.38 g) dissolved in 20 ml of tetrahydrofuran is added dropwise to a suspension of AlLiH₄ (2.4 g) in 130 ml of tetrahydrofuran cooled to 0° C. At the end of the addition, the mixture is heated at 60° C. for 45 minutes. The mixture is cooled and then hydrolysed using a 1N aqueous NaOH solution (12 ml). The insoluble matter is removed by filtering off and the filtrate is evaporated under vacuum. The residue is dissolved in 1N hydrochloric acid. The aqueous phase is washed with ethyl acetate and then rendered alkaline using 2N sodium hydroxide solution The product is extracted with ethyl acetate. The organic phase is dried over Na₂ SO₄ and then evaporated under reduced pressure. The desired product is crystallised from a petroleum ether/ethyl acetate (95/5) mixture and collected by filtering off=6.53 g (65%). [α]₅₇₈ ²⁰ =-67.1° (c=1, MeOH). m.p.= 89°-91° C.

b') N-benzoyl-2(S)-(4-methylpiperidinomethyl)-(S)-cyclohexylamine is obtained by the same procedure from the product obtained in a'). [α]₅₇₈ ²⁰ =+67.2°

m.p.=79.5°-84.5° C.

c) (R,R)-2-(4-methylpiperidinomethyl)-cyclohexylamine.

The product obtained in step b) (6.43 g) is dissolved in 55 ml of 6N HCl. The mixture is refluxed for 5 days. The mixture is extracted with ethyl acetate, rendered alkaline using a concentrated sodium hydroxide solution and extracted with three times 100 ml of ethyl acetate. The organic phase is dried over Na₂ SO₄ and then evaporated under reduced pressure. The diamine is obtained in the form of an oil (4.17 g; 97%). [α]_(D) ²⁰ =-25.2° (c=1, MeOH).

c') The same procedure yields (S,S) 2-(4-methylpiperidinomethyl) cyclohexylamine from the product obtained in b'). [α]_(D) ²⁰ =+25.2° (c=1, MeOH).

Results demonstrating the properties of the compounds of formula I in two tests, that is to say gastric emptying of solids and antagonism to stereotypy induced by apomorphine, are given below. The first test enables the activity of the product on the digestive motility to be demonstrated and the second permits confirmation of the absence of central dopaminergic antagonistic effects.

Activity on the digestive motility

Gastric emptying is studied in male Sprague Dawley rats weighing about 150 g. On day 0 a postdiaphragmatic vagotomy is carried out so as to create a retarded gastric emptying model. On day 7 the product to be tested or the placebo is administered to the animals oesophageally or intraperitoneally (T0). At T+15 minutes, n indigestible particles 1 mm in diameter are administered intragastrically. The animals are killed by euthanasia at T+3 h and the particles remaining in the stomach are counted. Gastric emptying is expressed by the percentage of particles having left the stomach.

It is less than 30% in the case of the rats which have undergone a vagotomy; in comparison, it is greater than 50% in the animals which have undergone a laparotomy only.

At least 3 doses are tested for each compound (the minimum of 10 animals per dose) and a positive control (metoclopramide, 5 mg kg⁻) is always carried out in parallel. The statistic comparisons make use of the Mann and Whitney non-parametric test.

The results obtained are given in Table III. When a product proves active, its minimum effective dose (MED) and the potentialisation (in the form of a multiple of the control value) observed at this dose are determined. If the product is active from the lowest dose tested, the MED is said to be less than or equal to (≦) this dose.

Central dopaminerqic antagonist activity

Stereotypy of the buccal sphere is induced in male Sprague Dawley rats weighing about 150 g by subcutaneous injection of apomorphine hydrochloride (1 mg kg⁻¹). The products to be studied are administered intraperitoneally 30 minutes before the injection of apomorphine. The animals are observed 15, 30, 45, 60, 75 and 90 minutes after this injection.

The stereotypy intensity is assessed using a grading system ranging from 0 (absence of abnormal movement) to 3 (licking and/or intense or permanent chewing) and expressed in the form of a cumulative score over a period of 90 minutes.

At least 2 doses are tested for each product (a minimum of 6 animals per dose) and a positive control (metoclopramide, 3 mg kg⁻¹) is always carried out in parallel. The statistical comparisons make use of the Mann and Whitney non-parametric test. The results obtained are given in Table III. If the products are inactive (IN), the highest dose tested is indicated; if a product proves active, the effective dose (ED) and the percentage inhibition observed are indicated.

                                      TABLE III                                    __________________________________________________________________________                              Antagonism to stereotypy                                      Gastric emptying of solids                                                                      induced by apomorphine                                Example MED (μgkg.sup.-1)                                                                   Potentialisation                                                                        ED (mgkg.sup.-1)                                      __________________________________________________________________________      2      ≦10                                                                             ×2.5                                                                             IN(3)                                                   3      30      ×2.5                                                                             IN(3)                                                   4      ≦10                                                                             ×3.4                                                                             IN(3)                                                   5      ≦30*                                                                            ×3.1                                                                             IN(3)                                                   6      300*    ×1.9                                                                             IN(3)                                                   7      ≦30                                                                             ×3.9                                                                             IN(3)                                                   8      ≦30                                                                             ×2.3                                                                             IN(3)                                                   9      ≦10                                                                             ×3.3                                                                             IN(3)                                                  10      ≦10                                                                             ×6.1                                                                             IN(3)                                                  11      ≦10                                                                             ×5.4                                                                             IN(3)                                                  12      30      ×2                                                                               IN(3)                                                  13      ≦30                                                                             ×4.2                                                                             IN(3)                                                  14      1000*   ×2.6                                                                             IN(3)                                                  15      30      ×5.7                                                                             IN(3)                                                  16      3000*   ×3.2                                                                             IN(3)                                                  Compound A                                                                             3000      ×1.18**                                                GB-A-1 015 921                                                                 17      30       1.5    IN(3)                                                  18      10       2.5     IN(10)                                                19      10       2.8    ND                                                     20      10       3.1    ND                                                     21      10       1.9    ND                                                     22      30       1.6    ND                                                     23      <10      1.7    IN(3)                                                  24      30       2      IN(3)                                                  25      30       1.7    IN(3)                                                  27      10       2.1    ND                                                     28      <10      2.1     IN(10)                                                29      30       2.7    ND                                                     30      10       1.9    IN(3)                                                  31      30       2.7    IN(3)                                                  32      50      ×7                                                                               IN(1)                                                  33      30       2.6    ND                                                     __________________________________________________________________________      *products studied after intraperitoneal administration                         **not significant                                                              ND: Not determined                                                       

The compounds of formula (I) may be used to stimulate the gastro-intestinal motility. They may be used to treat digestive disorders such as gastroparesis, gastro-oesophaeal reflux, dyspepsia, constipation and some forms of irritable colon or intestine syndrome.

These compounds or their addition salts obtained with pharmaceutically acceptable acids can be administered to man in the form of a wide variety of pharmaceutical compositions.

The present invention therefore also relates to therapeutic compositions comprising, as active principle, a compound of formula I or one of its addition salts with pharmaceutically acceptable acids.

The active principle may be administered orally, intravenously, subcutaneously or parenterally and in one of more administrations for a daily dose of 0.05 mg to 50 mg.

The therapeutic compositions may contain 0.05 to 50 mg of active principle per unit. For oral administration, they may be in the form of tablets or of capsules containing one of the excipients commonly used in the pharmaceutical sector. 

We claim:
 1. A compound selected from the compounds of the formula ##STR19## in which: R₁ is selected from C₁ -C₄ alkoxy, methoxy (C₁ -C₃ alkoxy), C₃ -C₄ alkenyloxy and C₅ -C₆ cycloalkoxy, or R₁ and R₂, in the 3-position, together and with the aromatic ring to which they are bonded form a 2,3-dihydrobenzofuran ring,R₂, R₃ and R₄ are selected independently of one another from hydrogen, halogen, hydroxy, C₁ -C₃ alkoxy, amino, (C₁ -C₃ alkyl)amino, di(C₁ -C₃ alkyl) amino and (C₁ -C₃ alkyl) carbonylamino, and Z is selected from piperidinyl and piperidinyl substituted in the 4-position by hydroxy, C₁ -C₃ alkoxy, hydroxyethyl, (C₁ -C₃ alkoxy)ethyl, (C₁ -C₃ alkoxy)methyl, C₁ -C₄ alkyl or two C₁ -C₃ alkyl,and their addition salts with pharmaceutically acceptable acids.
 2. A compound selected from the compounds of the formula: ##STR20## in which: R₁ is selected from C₁ -C₄ alkoxy, methoxy(C₁ -C₃ alkoxy), C₃ -C₄ alkenyloxy and C₅ -C₆ cycloalkoxy, or R₁ and R₂, in the 3-position, together and with the aromatic ring to which they are bonded form a 2,3-dihydrobenzofuran ring,R₂, R₃ and R₄ are selected independently of one another from hydrogen, halogen, hydroxy, C₁ -C₃ alkoxy, amino, (C₁ -C₃ alkyl)amino, di(C₁ -C₃ alkyl)amino and (C₁ -C₃ alkyl)carbonylamino, and Z is selected from piperidinyl and piperidinyl substituted in the 4-position by hydroxy, C₁ -C₃ alkoxy, (C₁ -C₃ alkoxy)ethyl, (C₁ -C₃ alkoxy)methyl groups, straight-chain or branched C₁ -C₄ alkyl or two C₁ -C₃ alkyl,and their addition salts with pharmaceutically acceptable acids.
 3. A compound according to claim 1, of the formula: ##STR21## in which R₁ is C₁ -C₄ alkoxy.
 4. A compound according to claim 3, in which R₁ is methoxy.
 5. A compound according to claim 3, in which R₁ is selected from ethoxy and cyclopropylmethoxy.
 6. A compound according to claim 3, in which Z is selected from piperidino, 4-methylpiperidino, 4,4-dimethylpiperidino and 4-hydroxypiperidino.
 7. A compound according to claim 6, of formula ##STR22## in which R₇ is methyl and R₁₀ is hydrogen.
 8. A compound according to claim 6, of formula ##STR23## in which R₇ and R₁₀ are methyl.
 9. A compound according to claim 6, of formula ##STR24## in which R₇ is hydroxy and R₁₀ hydrogen.
 10. A therapeutic composition having a stimulating activity on the gastro-intestinal motility comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.
 11. A process for stimulating the gastro-intestinal motility which comprises administering to a human in need thereof an effective amount of a compound according to claim
 1. 